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Rationale: Asthma is characterized by disease within the small airways. Several studies have suggested that forced oscillation technique–derived resistance at 5 Hz (R5) − resistance at 20 Hz (R20) is a measure of small airway disease; however, there has been limited validation of this measurement to date. Objectives: To validate the use of forced oscillation R5 − R20 as a measure of small airway narrowing in asthma, and to investigate the role that small airway narrowing plays in asthma. Methods: Patient-based complete conducting airway models were generated from computed tomography scans to simulate the impact of different degrees of airway narrowing at different levels of the airway tree on forced oscillation R5 − R20 (n = 31). The computational models were coupled with regression models in an asthmatic cohort (n = 177) to simulate the impact of small airway narrowing on asthma control and quality of life. The computational models were used to predict the impact on small airway narrowing of type-2 targeting biologics using pooled data from two similarly design randomized, placebo-controlled biologic trials (n = 137). Measurements and Main Results: Simulations demonstrated that narrowing of the small airways had a greater impact on R5 − R20 than narrowing of the larger airways and was associated (above a threshold of approximately 40% narrowing) with marked deterioration in both asthma control and asthma quality of life, above the minimal clinical important difference. The observed treatment effect on R5 − R20 in the pooled trials equated to a predicted small airway narrowing reversal of approximately 40%. Conclusions: We have demonstrated, using computational modeling, that forced oscillation R5 − R20 is a direct measure of anatomical narrowing in the small airways and that small airway narrowing has a marked impact on both asthma control and quality of life and may be modified by biologics.

Resistive breathing is associated with large negative intrathoracic pressures. Increased mechanical stress induces high-permeability pulmonary edema and lung inflammation.To determine the effects of resistive breathing on the healthy lung.Anesthetized rats breathed through a two-way nonrebreathing valve. The inspiratory line was connected to a resistance setting peak inspiratory tracheal pressure at 50% of maximum (inspiratory resistive breathing), while 100% oxygen was supplied to prevent hypoxemia. Quietly breathing animals (100% oxygen) served as controls. Lung injury was evaluated after 3 and 6 hours of resistive breathing.After both 3 and 6 hours of resistive breathing, lung permeability was increased, as assessed by (99m)Tc-diethylenetriaminepentaacetic acid scintigraphy and Evans blue dye extravasation. Tissue elasticity, measured on the basis of static pressure-volume curves and by the low-frequency forced oscillation technique, was also increased. After both 3 and 6 hours of resistive breathing, gravimetric measurements revealed the presence of pulmonary edema and analysis of bronchoalveolar lavage showed increased total protein content, whereas the total cell count was elevated only after 6 hours of resistive breathing. Cytokine levels were assessed in bronchoalveolar lavage fluid and lung tissue by ELISA and were increased after 6 hours compared with controls. Western blot analysis showed early activation of Src kinase via phosphorylation (at 30 min), and Erk1/2 and IκBα (nuclear factor-κB inhibitor) were phosphorylated at 3 and 6 hours. Pathology revealed the presence of lung injury after resistive breathing.Resistive breathing induces acute lung injury and inflammation.

Reduced airway distensibility in subjects with asthma compared with control subjects may be related to differences in lung elastic recoil and bronchomotor tone.To examine the contribution of lung elastic recoil and bronchomotor tone to airway distensibility.We compared airway distensibility in 18 subjects with asthma with 19 control subjects before and after bronchodilator administration and, in a subgroup of 7 subjects with asthma and 8 control subjects, correlated distensibility with pressure-volume parameters.Distensibility was measured, using the forced oscillation technique, as the linear slope of conductance versus volume between total lung capacity (TLC) and 75% TLC and between 75% TLC and FRC. Transpulmonary pressure was recorded concurrently with distensibility, using an esophageal balloon. Pressure-conductance data were described using linear regressions and pressure-volume data were described using exponential equations. Subjects with asthma had lower baseline FEV1 (p=0.0003) and conductance (p=0.002) than did control subjects. Distensibility above 75% TLC was less in subjects with asthma than in control subjects (p0.0001), but there was no difference below 75% TLC. Bronchodilator administration did not alter distensibility despite increases in FEV1 (p=0.0002) and conductance (p0.0001) in subjects with asthma, and conductance (p=0.0004) in control subjects. After bronchodilator administration, subjects with asthma had reduced lung elastic recoil compared with control subjects (p=0.03) and a reduced pressure-conductance slope (p=0.01), but there were no correlations between pressure-volume characteristics and airway distensibility.Airway distensibility measured by forced oscillation technique is reduced in subjects with asthma compared with subjects without asthma, is not related to lung elastic recoil, and is unchanged by bronchodilator administration. Airway wall remodeling remains the most likely cause of reduced airway distensibility in asthma.

The forced oscillation technique (FOT) is particularly attractive in a pediatric setting as it requires only passive cooperation from the child. We assessed the sensitivity and specificity of this method for detecting airway obstruction and its reversibility in 313 children (3 to 16 yr of age) with asthma or chronic nocturnal cough. Baseline and postbronchodilator (n 5 251) resistance were measured (R 0 ) with the FOT. Baseline R 0 was normalized for height and weight [R 0 (SD)]. In children able to perform forced expiratory maneuvers (n 5 181), R 0 (SD) was independently correlated with FEV 1 (p , 0.02) and maximal expiratory flow at 50% (MEF 50 ) (p , 0.004). The optimal R 0 (SD) cutoff value given by receiver operating characteristic (ROC) curves to discriminate between children with baseline FEV 1 , 80% or > 80% of predicted values yielded 84% sensitivity and 73% specificity. Postbronchodilator changes in R 0 (SD) [ D R 0 (SD)] were mostly correlated to changes in MEF 50 . The optimal D R 0 (SD) cutoff value to discriminate between children with the presence or absence of significant reversibility in FEV 1 yielded 69% sensitivity and 78% specificity. In children unable to perform forced expiratory maneuvers (n 5 132), this D R 0 (SD) cutoff clearly identified a subgroup of young children with high R 0 values at baseline, that returned to normal after bronchodilation. We conclude that FOT measurements allow reliable evaluation of bronchial obstruction and its reversibility in asthmatic children over 3 yr old. Delacourt C, Lorino H, Herve-Guillot M, Reinert P, Harf A, Housset B. Use of the forced oscillation technique to assess airway obstruction and reversibility in children. AM J RESPIR CRIT CARE MED 2000;161:730‐736. The detection of airflow obstruction and its reversibility is a routine procedure in pediatric pulmonary function laboratories. Measurement of forced expiratory volume in one second (FEV 1 ) is considered to be the basic test for the assessment of airway obstruction. However, it is usually difficult to obtain in children younger than 6 yr of age because it is effort-dependent and therefore requires active cooperation from the child. An alternative method is measurement of the total resistance of the respiratory system (Rrs) with the forced oscillation technique (FOT). This method is particularly attractive as it requires only passive cooperation from the subject, who breathes quietly at tidal volume during the test. In children, the FOT has already proved useful for evaluating bronchial responsiveness to nonspecific agents (1‐3). In contrast, few studies have evaluated the ability of this method to detect bronchial obstruction in children and to assess changes following bronchodilator inhalation (4‐6). Moreover, there is no consensus on Rrs criteria for the identification and grading of airway obstruction. A significant correlation has been found between baseline FEV 1 and Rrs (4, 6), but it was also suggested that

The forced oscillation technique (FOT) is a noninvasive method to measure respiratory resistance (Rrs) potentially useful for monitoring upper airway obstruction in patients with obstructive sleep apnea/hypopnea syndrome (SAHS). The aim of this work was to test the clinical suitability of FOT in assessing dynamic changes in airflow obstruction in patients with SAHS during continuous positive airway pressure (CPAP) and to investigate the CPAP dependence of Rrs. Forced oscillation (5 Hz) was applied to six male patients with SAHS submitted to CPAP titration procedure. Esophageal pressure was measured with a balloon-tipped catheter. Mid-inspiratory resistance (Rrs,i), mid-expiratory resistance (Rrs,e), and esophageal pressure swings (deltaPes) were computed for the respiratory events recorded at each CPAP level. Rrs,i decreased markedly and significantly from 36.0 +/- 4.0 cm H2O x s/L (mean +/- SEM) at baseline CPAP (4 cm H2O) to 13.1 +/- 2.8 cm H2O x s/L at optimal CPAP (11.3 +/- 0.4 cm H2O). Rrs,e showed a faster decrease with increasing CPAP reaching normal values at approximately 8 cm H2O. Rrs,i was strongly correlated (r2 = 0.94) with deltaPes. Our results suggest that FOT can be used as an alternative to the esophageal balloon for assessing airflow obstruction in patients with SAHS and for CPAP titration. Moreover, FOT allows us to detect phasic changes in resistance within the breathing cycle.

Respiratory transfer impedance (Ztr) measured using the forced oscillation technique requires virtually no patient cooperation and provides a noninvasive approach for acquiring data reflective of lung mechanics. Also, model analysis of Ztr provides reliable estimates of separate airway and tissue properties (1), but only if data out to 64 Hz are acquired. The current study evaluated the clinical utility of Ztr from 1-80 Hz for assessing the degree and type of impaired lung function. Spirometry and Ztr measurements were made on 37 individuals: 11 healthy subjects and 26 patients with lung disease including chronic obstructive pulmonary disease (COPD), asthma, lung cancer, and sarcoidosis. Over the entire patient group, 12 were also smokers. We first established normal ranges for several Ztr features and model estimated mechanical properties. The COPD and smokers groups showed significant differences in portions of their Ztr spectra from that of the healthy group. Key Ztr spectral features included R0, the frequency at which the real part of impedance is zero; and Re4, the real part of impedance at 4 Hz. The key model parameter was airway resistance, Raw. We found Raw, Re4, and R0 to be significantly elevated during disease (p0.0005) and to significantly decrease with bronchodilator therapy (p0.025). Moreover, we found moderate to strong correlations between R0, Raw, and Re4 versus FVC and R0 versus FEV1. After bronchodilator, changes in R0, Re4, and Raw were correlated with changes in several spirometric indices. The R0 feature has not been previously evaluated since it is typically above 32 Hz (well above 32 Hz in diseased individuals) and not encompassed in previous clinical studies.

Assessment of upper airway mechanics in patients with obstructive sleep apnea/hypopnea (OSA) can be carried out qualitatively from indirect signals (flow pattern, snoring, strain gauges, inductance plethysmography) or quantitatively by means of invasive estimation of esophageal pressure. The forced oscillation technique (FOT) is a noninvasive method of potential interest for quantitatively assessing airway obstruction in the sleeping patient. The aim of this work was to ascertain in a model study whether FOT could provide an index of airway obstruction when applied at the conditions of total and partial occlusions similar to the ones found in patients with OSA. An airway analog closely mimicking upper airway collapsibility was constructed and mechanically characterized by the relationship between its flow, upstream and downstream pressures as well as by means of FOT. We simulated total collapse (apnea), different levels of partial collapse with flow limitation (hypopnea), and release of airway obstruction when the collapsible analog was used as an artificial upper airway in a spontaneously breathing subject submitted to continuous positive airway pressure (CPAP) up to 14 cm H2O.s/L. The results showed that the amplitude of airway impedance measured by FOT was a suitable index to detect obstruction in collapsible segments. We concluded from this realistic model study that FOT could be a valuable tool for quantitatively assessing airway obstruction in patients with OSA treated with CPAP. This noninvasive technique is potentially useful both in studying upper airway mechanics in detail and in automatically monitoring airway obstruction in routine studies.

Rationale : The lungs continue to grow postnatally until adulthood. This growth is reflected in longitudinal changes in lung function whereby lung function "improves" with age before peaking in early adulthood. Early postnatal life has been identified as a time when susceptibility to respiratory insults is high due to the rapid growth of the lung during this time. However, while age dependent changes in lung function are typically modelled as smooth curves when plotted against height (as a proxy for lung size), additional periods of rapid somatic growth occur between birth and adulthood; particularly during puberty. Changes in lung function and growth during periods of rapid adolescent growth are poorly characterised. We aimed to examine age dependent changes in lung function in healthy mice and to correlate these changes with lung structure. Methods : 2, 4, 6 and 8 week old naive C57BL/6 mice were assessed for somatic growth (weight and body length), lung mechanics and lung volume. Lung mechanics and lung volume were measured in anaesthetised, tracheostomised and mechanically ventilated mice using a modification of the forced oscillation technique and plethysmography respectively. The respiratory system impedance was partitioned into parameters representing the airway (airway resistance, R ) and tissue (tissue damping, G; tissue elastance, H; hysteresivity = G/H) aw mechanics. Lungs were fixed and structure was assessed histologically according to ATS/ERS guidelines. Results : Lung volume increased with age while R , G and H decreased. Lung volume and R were linearly associated with body length aw aw in the 2 and 8 week old mice, however there was no relationship between R (p = 0.12) or lung volume (p = 0.165), and age in 4 and 6 aw week old mice despite substantial increases in body length. In contrast, both G (p Conclusions : The substantial change in tissue mechanics without a corresponding increase in lung volume during adolescence in mice suggests that this stage represents a time of rapid parenchymal restructuring. Such rapid growth may lead to increased susceptibility to respiratory insults.

The potential of the forced oscillation technique to detect the airway response on histamine bronchial challenge tests was compared with that of FEV1 and plethysmographic SGaw. In 53 subjects with a history of episodic wheezing and a normal baseline airway resistance, we carried out bronchial challenges with successively doubling concentrations of histamine until FEV1 had dropped by 15% or more or a concentration of 16 mg/ml histamine was reached. For the baseline values, a mean within-subject coefficient of variation was found of 2.8% for FEV1, 7.4% for SGaw, 8.7% for the oscillatory respiratory conductance at 6 Hz (1/Rrs6), and 7.7% for the mean oscillatory respiratory conductance (between 2 and 26 Hz) (1/Rrs). The latter coefficients allow the calculation of the following threshold values: PD15FEV1, PD40SGaw, PD47 1/Rrs6, and PD42 1/Rrs. The probability of exceeding these levels by chance is virtually zero. Histamine challenge caused significant absolute changes in Rrs at 6 Hz (Rrs6), in mean level of Rrs and of respiratory reactance (Xrs), in slope of Rrs and Xrs versus frequency, and in mean curvature of Rrs-frequency curve. A multivariate analysis of the differences between prechallenge and postchallenge values showed that the parameters with the best sensitivity to detect the effect of histamine were, in decreasing order: the relative change of SGaw, of 1/Rrs6, of 1/Rrs, of FEV1, of FVC, and of 1/Vtg, followed by the absolute change of Xrs and of the average slope of the Rrs-frequency relationship.(ABSTRACT TRUNCATED AT 250 WORDS)